We have shown that the rabbit disc degeneration model, which is induced by puncturing the annulus[unreadable] fibrosus with needles of defined gauges, resulted in reproducible, degenerative changes that could be[unreadable] quantitatively assessed. Our initial hypothesis that an injection of the growth factor, osteogenic protein-1, is[unreadable] able to regenerate the intervertebral disc was shown to be true using this model. This promising protein[unreadable] injection therapy approach will soon be translated into a Phase I clinical trial as the first injection therapy[unreadable] using a growth factor. The approaches in the proposed funding period are to: (1) test if the injection of a[unreadable] growth factor into a disc also stimulates repair in a more clinically relevant model using adult rabbits; (2)[unreadable] expand therapeutic approaches to the application of cytokine inhibitory molecules; and (3) delineate the[unreadable] limitations of such therapy under conditions where nutrition levels in the disc are compromised. In addition,[unreadable] efforts will be extended to identify changes in nerve-related cytokines, i.e. nerve growth factor, in the rabbit[unreadable] model and in cadaveric samples, as potential surrogate markers of low back pain. Hypothesis 1: Disc[unreadable] degeneration can be delayed or reversed by manipulating the balance between anabolic and catabolic[unreadable] pathways; some manipulations will result in decreased pain associated with disc degeneration. In Specific[unreadable] Aim 1, we will test if growth factors (osteogenic protein-1, growth differentiation factor-5) and/or inhibitory[unreadable] molecules of cytokines (interleukin-1 receptor antagonist, tumor necrosis factor-a soluble receptor) delay the[unreadable] progression of disc degeneration or restore the degenerated disc using an in vivo protein injection in a[unreadable] mature rabbit chronic disc degeneration model. Hypothesis 2: Compromised nutrient transport through the[unreadable] endplate limits cell-mediated disc repair induced by the application of a growth factor. In Specific Aim 2 we[unreadable] will investigate changes in nutrient transport in the rabbit annular puncture model of disc degeneration and[unreadable] identify the presence of a critical level of nutrient transport that is deleterious to matrix metabolism. Low back[unreadable] pain is responsible for enormous human suffering, high health care costs and significant socioeconomic[unreadable] losses. Although the etiology of back pain is often unknown, the intervertebral disc is a significant source of[unreadable] back problems. The results from this study will advance the field of biological treatment for intervertebral[unreadable] disc degeneration.